Browsing by Author "Brand, Randall E."
Now showing 1 - 8 of 8
Results Per Page
Sort Options
Item A Reduced Pancreatic Polypeptide Response is Associated With New-onset Pancreatogenic Diabetes Versus Type 2 Diabetes(The Endocrine Society, 2023) Hart, Phil A.; Kudva, Yogish C.; Yadav, Dhiraj; Andersen, Dana K.; Li, Yisheng; Toledo, Frederico G. S.; Wang, Fuchenchu; Bellin, Melena D.; Bradley, David; Brand, Randall E.; Cusi, Kenneth; Fisher, William; Mather, Kieren; Park, Walter G.; Saeed, Zeb; Considine, Robert V.; Graham, Sarah C.; Rinaudo, Jo Ann; Serrano, Jose; Goodarzi, Mark O.; Medicine, School of MedicinePurpose: Pancreatogenic diabetes refers to diabetes mellitus (DM) that develops in the setting of a disease of the exocrine pancreas, including pancreatic ductal adenocarcinoma (PDAC) and chronic pancreatitis (CP). We sought to evaluate whether a blunted nutrient response of pancreatic polypeptide (PP) can differentiate these DM subtypes from type 2 DM (T2DM). Methods: Subjects with new-onset DM (<3 years' duration) in the setting of PDAC (PDAC-DM, n = 28), CP (CP-DM, n = 38), or T2DM (n = 99) completed a standardized mixed meal tolerance test, then serum PP concentrations were subsequently measured at a central laboratory. Two-way comparisons of PP concentrations between groups were performed using Wilcoxon rank-sum test and analysis of covariance while adjusting for age, sex, and body mass index. Results: The fasting PP concentration was lower in both the PDAC-DM and CP-DM groups than in the T2DM group (P = 0.03 and <0.01, respectively). The fold change in PP at 15 minutes following meal stimulation was significantly lower in the PDAC-DM (median, 1.869) and CP-DM (1.813) groups compared with T2DM (3.283; P < 0.01 for both comparisons). The area under the curve of PP concentration was significantly lower in both the PDAC-DM and CP-DM groups than in T2DM regardless of the interval used for calculation and remained significant after adjustments. Conclusions: Fasting PP concentrations and the response to meal stimulation are reduced in new-onset DM associated with PDAC or CP compared with T2DM. These findings support further investigations into the use of PP concentrations to characterize pancreatogenic DM and to understand the pathophysiological role in exocrine pancreatic diseases.Item Acute pancreatitis precedes chronic pancreatitis in the majority of patients: Results from the NAPS2 consortium(Elsevier, 2022-12) Singh, Vikesh K.; Whitcomb, David C.; Banks, Peter A.; AlKaade, Samer; Anderson, Michelle A.; Amann, Stephen T.; Brand, Randall E.; Conwel, Darwin L.; Cote, Gregory A.; Gardner, Timothy B.; Gelrud, Andres; Guda, Nalini; Forsmark, Christopher E.; Lewis, Michele; Sherman, Stuart; Muniraj, Thiruvengadam; Romagnuolo, Joseph; Tan, Xiaoqing; Tang, Gong; Sandhu, Bimaljit S.; Slivka, Adam; Wilcox, C. Mel; Yadav, Dhiraj; Medicine, School of MedicineIntroduction: The mechanistic definition of chronic pancreatitis (CP) identifies acute pancreatitis (AP) as a precursor stage. We hypothesized that clinical AP frequently precedes the diagnosis of CP and is associated with patient- and disease-related factors. We describe the prevalence, temporal relationship and associations of AP in a well-defined North American cohort. Methods: We evaluated data from 883 patients with CP prospectively enrolled in the North American Pancreatitis Studies across 27 US centers between 2000 and 2014. We determined how often patients had one or more episodes of AP and its occurrence in relationship to the diagnosis of CP. We used multivariable logistic regression to determine associations for prior AP. Results: There were 624/883 (70.7%) patients with prior AP, among whom 161 (25.8%) had AP within 2 years, 115 (18.4%) within 3–5 years, and 348 (55.8%) >5 years prior to CP diagnosis. Among 504 AP patients with available information, 436 (86.5%) had >1 episode. On multivariable analyses, factors associated with increased odds of having prior AP were a younger age at CP diagnosis, white race, abdominal pain, pseudocyst(s) and pancreatic duct dilatation/stricture, while factors associated with a lower odds of having prior AP were exocrine insufficiency and pancreatic atrophy. When compared with patients with 1 episode, those with >1 AP episode were diagnosed with CP an average of 5 years earlier. Conclusions: Nearly three-quarters of patients were diagnosed with AP prior to CP diagnosis. Identifying which AP patients are at-risk for future progression to CP may provide opportunities for primary and secondary prevention.Item Chronic pancreatitis: Pediatric and adult cohorts show similarities in disease progress despite different risk factors(Lippincott, Williams & Wilkins, 2020-04) Schwarzenberg, Sarah J.; Uc, Aliye; Zimmerman, Bridget; Wilschanski, Michael; Wilcox, C. Mel; Whitcomb, David C.; Werlin, Steven L.; Troendle, David; Tang, Gong; Slivka, Adam; Singh, Vikesh K.; Sherman, Stuart; Shah, Uzma; Sandhu, Bimaljit S.; Romagnuolo, Joseph; Rhee, Sue; Pohl, John F.; Perito, Emily R.; Ooi, Chee Y.; Nathan, Jaimie D.; Muniraj, Thiruvengadam; Morinville, Veronique D.; McFerron, Brian; Mascarenhas, Maria; Maqbool, Asim; Liu, Quin; Lin, Tom K.; Lewis, Michele; Husain, Sohail Z.; Himes, Ryan; Heyman, Melvin B.; Guda, Nalini; Gonska, Tanja; Giefer, Matthew J.; Gelrud, Andres; Gariepy, Cheryl E.; Gardner, Timothy B.; Freedman, Steven D.; Forsmark, Christopher E.; Fishman, Douglas S.; Cote, Gregory A.; Conwell, Darwin; Brand, Randall E.; Bellin, Melena; Barth, Bradley; Banks, Peter A.; Anderson, Michelle A.; Amann, Stephen T.; Alkaade, Samer; Abu-El-Haija, Maisam; Abberbock, Judah N.; Lowe, Mark E.; Yadav, Dhiraj; Medicine, School of MedicineObjectives: To investigate the natural history of chronic pancreatitis (CP), patients in the North American Pancreatitis Study2 (NAPS2, adults) and INternational Study group of Pediatric Pancreatitis: In search for a cuRE (INSPPIRE, pediatric) were compared. Methods: Demographics, risk factors, disease duration, management and outcomes of 224 children and 1,063 adults were compared using appropriate statistical tests for categorical and continuous variables. Results: Alcohol was a risk in 53% of adults and 1% of children (p<0.0001); tobacco in 50% of adults and 7% of children (p<0.0001). Obstructive factors were more common in children (29% vs 19% in adults, p=0.001). Genetic risk factors were found more often in children. Exocrine pancreatic insufficiency was similar (children 26% vs adult 33%, p=0.107). Diabetes was more common in adults than children (36% vs 4% respectively, p<0.0001). Median emergency room visits, hospitalizations, and missed days of work/school were similar across the cohorts. As a secondary analysis, NAPS2 subjects with childhood onset (NAPS2-CO) were compared to INSPPIRE subjects. These two cohorts were more similar than the total INSPPIRE and NAPS2 cohorts, including for genetic risk factors. The only risk factor significantly more common in the NAPS2-CO cohort compared with the INSPPIRE cohort was alcohol (9% NAPS2-CO vs 1% INSPPIRE cohorts, p=0.011). Conclusions: Despite disparity in age of onset, children and adults with CP exhibit similarity in demographics, CP treatment, and pain. Differences between groups in radiographic findings and diabetes prevalence may be related to differences in risk factors associated with disease and length of time of CP.Item Delphi Initiative for Early-Onset Colorectal Cancer (DIRECt) International Management Guidelines(Elsevier, 2023) Cavestro, Giulia Martina; Mannucci, Alessandro; Balaguer, Francesc; Hampel, Heather; Kupfer, Sonia S.; Repici, Alessandro; Sartore-Bianchi, Andrea; Seppälä, Toni T.; Valentini, Vincenzo; Boland, Clement Richard; Brand, Randall E.; Buffart, Tineke E.; Burke, Carol A.; Caccialanza, Riccardo; Cannizzaro, Renato; Cascinu, Stefano; Cercek, Andrea; Crosbie, Emma J.; Danese, Silvio; Dekker, Evelien; Daca-Alvarez, Maria; Deni, Francesco; Dominguez-Valentin, Mev; Eng, Cathy; Goel, Ajay; Guillem, Josè G.; Houwen, Britt B. S. L.; Kahi, Charles; Kalady, Matthew F.; Kastrinos, Fay; Kühn, Florian; Laghi, Luigi; Latchford, Andrew; Liska, David; Lynch, Patrick; Malesci, Alberto; Mauri, Gianluca; Meldolesi, Elisa; Møller, Pål; Monahan, Kevin J.; Möslein, Gabriela; Murphy, Caitlin C.; Nass, Karlijn; Ng, Kimmie; Oliani, Cristina; Papaleo, Enrico; Patel, Swati G.; Puzzono, Marta; Remo, Andrea; Ricciardiello, Luigi; Ripamonti, Carla Ida; Siena, Salvatore; Singh, Satish K.; Stadler, Zsofia K.; Stanich, Peter P.; Syngal, Sapna; Turi, Stefano; Urso, Emanuele Damiano; Valle, Laura; Vanni, Valeria Stella; Vilar, Eduardo; Vitellaro, Marco; You, Yi-Qian Nancy; Yurgelun, Matthew B.; Zuppardo, Raffaella Alessia; Stoffel, Elena M.; Associazione Italiana Familiarità Ereditarietà Tumori; Collaborative Group of the Americas on Inherited Gastrointestinal Cancer; European Hereditary Tumour Group; International Society for Gastrointestinal Hereditary Tumours; Medicine, School of MedicineBackground & aims: Patients with early-onset colorectal cancer (eoCRC) are managed according to guidelines that are not age-specific. A multidisciplinary international group (DIRECt), composed of 69 experts, was convened to develop the first evidence-based consensus recommendations for eoCRC. Methods: After reviewing the published literature, a Delphi methodology was used to draft and respond to clinically relevant questions. Each statement underwent 3 rounds of voting and reached a consensus level of agreement of ≥80%. Results: The DIRECt group produced 31 statements in 7 areas of interest: diagnosis, risk factors, genetics, pathology-oncology, endoscopy, therapy, and supportive care. There was strong consensus that all individuals younger than 50 should undergo CRC risk stratification and prompt symptom assessment. All newly diagnosed eoCRC patients should receive germline genetic testing, ideally before surgery. On the basis of current evidence, endoscopic, surgical, and oncologic treatment of eoCRC should not differ from later-onset CRC, except for individuals with pathogenic or likely pathogenic germline variants. The evidence on chemotherapy is not sufficient to recommend changes to established therapeutic protocols. Fertility preservation and sexual health are important to address in eoCRC survivors. The DIRECt group highlighted areas with knowledge gaps that should be prioritized in future research efforts, including age at first screening for the general population, use of fecal immunochemical tests, chemotherapy, endoscopic therapy, and post-treatment surveillance for eoCRC patients. Conclusions: The DIRECt group produced the first consensus recommendations on eoCRC. All statements should be considered together with the accompanying comments and literature reviews. We highlighted areas where research should be prioritized. These guidelines represent a useful tool for clinicians caring for patients with eoCRC.Item Global protease activity profiling provides differential diagnosis of pancreatic cysts(American Association for Cancer Research, 2017-08-15) Ivry, Sam L.; Sharib, Jeremy M.; Dominguez, Dana A.; Roy, Nilotpal; Hatcher, Stacy E.; Yip-Schneider, Michele T.; Schmidt, C. Max; Brand, Randall E.; Park, Walter G.; Hebrok, Matthias; Kim, Grace E.; O'Donoghue, Anthony J.; Kirkwood, Kimberly S.; Craik, Charles S.; Surgery, School of MedicinePurpose: Pancreatic cysts are estimated to be present in 2%-3% of the adult population. Unfortunately, current diagnostics do not accurately distinguish benign cysts from those that can progress into invasive cancer. Misregulated pericellular proteolysis is a hallmark of malignancy, and therefore, we used a global approach to discover protease activities that differentiate benign nonmucinous cysts from premalignant mucinous cysts.Experimental Design: We employed an unbiased and global protease profiling approach to discover protease activities in 23 cyst fluid samples. The distinguishing activities of select proteases was confirmed in 110 samples using specific fluorogenic substrates and required less than 5 μL of cyst fluid.Results: We determined that the activities of the aspartyl proteases gastricsin and cathepsin E are highly increased in fluid from mucinous cysts. IHC analysis revealed that gastricsin expression was associated with regions of low-grade dysplasia, whereas cathepsin E expression was independent of dysplasia grade. Gastricsin activity differentiated mucinous from nonmucinous cysts with a specificity of 100% and a sensitivity of 93%, whereas cathepsin E activity was 92% specific and 70% sensitive. Gastricsin significantly outperformed the most widely used molecular biomarker, carcinoembryonic antigen (CEA), which demonstrated 94% specificity and 65% sensitivity. Combined analysis of gastricsin and CEA resulted in a near perfect classifier with 100% specificity and 98% sensitivity.Conclusions: Quantitation of gastricsin and cathepsin E activities accurately distinguished mucinous from nonmucinous pancreatic cysts and has the potential to replace current diagnostics for analysis of these highly prevalent lesions. Clin Cancer Res; 23(16); 4865-74. ©2017 AACR.Item A multimodality test to guide the management of patients with a pancreatic cyst(American Association for the Advancement of Science, 2019-07-17) Springer, Simeon; Masica, David L.; Dal Molin, Marco; Douville, Christopher; Thoburn, Christopher J.; Afsari, Bahman; Li, Lu; Cohen, Joshua D.; Thompson, Elizabeth; Allen, Peter J.; Klimstra, David S.; Schattner, Mark A.; Schmidt, C. Max; Yip-Schneider, Michele; Simpson, Rachel E.; Castillo, Carlos Fernandez-Del; Mino-Kenudson, Mari; Brugge, William; Brand, Randall E.; Singhi, Aatur D.; Scarpa, Aldo; Lawlor, Rita; Salvia, Roberto; Zamboni, Giuseppe; Hong, Seung-Mo; Hwang, Dae Wook; Jang, Jin-Young; Kwon, Wooil; Swan, Niall; Geoghegan, Justin; Falconi, Massimo; Crippa, Stefano; Doglioni, Claudio; Paulino, Jorge; Schulick, Richard D.; Edil, Barish H.; Park, Walter; Yachida, Shinichi; Hijioka, Susumu; van Hooft, Jeanin; He, Jin; Weiss, Matthew J.; Burkhart, Richard; Makary, Martin; Canto, Marcia I.; Goggins, Michael G.; Ptak, Janine; Dobbyn, Lisa; Schaefer, Joy; Sillman, Natalie; Popoli, Maria; Klein, Alison P.; Tomasetti, Cristian; Karchin, Rachel; Papadopoulos, Nickolas; Kinzler, Kenneth W.; Vogelstein, Bert; Wolfgang, Christopher L.; Hruban, Ralph H.; Lennon, Anne Marie; Surgery, School of MedicinePancreatic cysts are common and often pose a management dilemma, because some cysts are precancerous, whereas others have little risk of developing into invasive cancers. We used supervised machine learning techniques to develop a comprehensive test, CompCyst, to guide the management of patients with pancreatic cysts. The test is based on selected clinical features, imaging characteristics, and cyst fluid genetic and biochemical markers. Using data from 436 patients with pancreatic cysts, we trained CompCyst to classify patients as those who required surgery, those who should be routinely monitored, and those who did not require further surveillance. We then tested CompCyst in an independent cohort of 426 patients, with histopathology used as the gold standard. We found that clinical management informed by the CompCyst test was more accurate than the management dictated by conventional clinical and imaging criteria alone. Application of the CompCyst test would have spared surgery in more than half of the patients who underwent unnecessary resection of their cysts. CompCyst therefore has the potential to reduce the patient morbidity and economic costs associated with current standard-of-care pancreatic cyst management practices.Item A Prospective Study to Establish a New-Onset Diabetes Cohort: From the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer(Wolters Kluwer, 2018-11) Maitra, Anirban; Sharma, Ayush; Brand, Randall E.; Van Den Eeden, Stephen K.; Fisher, William E.; Hart, Phil A.; Hughes, Steven J.; Mather, Kieren J.; Pandol, Stephen J.; Park, Walter G.; Feng, Ziding; Serrano, Jose; Rinaudo, Jo Ann; Srivastava, Sudhir; Chari, Suresh T.; Medicine, School of MedicineThe National Cancer Institute and the National Institute for Diabetes and Digestive and Kidney Diseases initiated the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC) in 2015 (the CPDPC's origin, structure, governance, and research objectives are described in another article in this journal). One of the key objectives of CPDPC is to assemble a cohort of 10,000 subjects 50 years or older with new-onset diabetes, called the NOD cohort. Using a define, enrich, and find early detection approach, the aims of the NOD study are to (a) estimate the 3-year probability of pancreatic ductal adenocarcinoma (PDAC) in NOD (define), (b) establish a biobank of clinically annotated biospecimens from presymptomatic PDAC and control new-onset type 2 diabetes mellitus subjects, (c) conduct phase 3 validation studies of promising biomarkers for identification of incident PDAC in NOD patients (enrich), and (d) provide a platform for development of a future interventional screening protocol for early detection of PDAC in patients with NOD that incorporates imaging studies and/or clinical algorithms (find). It is expected that 85 to 100 incidences of PDAC will be diagnosed during the study period in this cohort of 10,000 patients.Item Serum biomarkers for chronic pancreatitis pain patterns(Elsevier, 2021) Saloman, Jami L.; Tang, Gong; Stello, Kimberly M.; Hall, Kristen E.; Wang, Xianling; AlKaade, Samer; Banks, Peter A.; Brand, Randall E.; Conwell, Darwin L.; Coté, Gregory A.; Forsmark, Christopher E.; Gardner, Timothy B.; Gelrud, Andres; Lewis, Michele D.; Sherman, Stuart; Slivka, Adam; Whitcomb, David C.; Yadav, Dhiraj; NAPS consortium; Medicine, School of MedicineObjectives: Chronic pancreatitis (CP) is associated with debilitating refractory pain. Distinct subtypes of CP pain have been previously characterized based on severity (none, mild-moderate, severe) and temporal (none, intermittent, constant) nature of pain, but no mechanism-based tools are available to guide pain management. This exploratory study was designed to determine if potential pain biomarkers could be detected in patient serum and whether they associate with specific pain patterns. Methods: Cytokines, chemokines, and peptides associated with nociception and pain were measured in legacy serum samples from CP patients (N = 99) enrolled in the North American Pancreatitis Studies. The unsupervised hierarchical cluster analysis was applied to cluster CP patients based on their biomarker profile. Classification and regression tree was used to assess whether these biomarkers can predict pain outcomes. Results: The hierarchical cluster analysis revealed a subset of patients with predominantly constant, mild-moderate pain exhibited elevated interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-2 (IL-2), tumor necrosis factor alpha (TNFα), and monocyte chemoattractant protein-1 (MCP1) whereas patients with higher interleukin-4 (IL-4), interleukin-8 (IL-8) and calcitonin gene related peptide (CGRP) were more likely to have severe pain. Interestingly, analyses of each individual biomarker revealed that patients with constant pain had reduced circulating TNFα and fractalkine. Patients with severe pain exhibited a significant reduction in TNFα as well as trends towards lower levels of IL-6 and substance P. Discussion: The observations from this study indicate that unique pain experiences within the chronic pancreatitis population can be associated with distinct biochemical signatures. These data indicate that further hypothesis-driven analyses combining biochemical measurements and detailed pain phenotyping could be used to develop precision approaches for pain management in patients with chronic pancreatitis.